Journal Article

DKFZ-2025-01050

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CD8+ T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells.

Schiele, P. ; Japp, A. S. ; Stark, R. ; Sattelberg, J. J. ; Nikolaou, C. ; Kornhuber, G. ; Abbasi, P. ; Ding, N. ; Rosnev, S. ; Meinke, S. ; Mühle, K. ; Loyal, L. ; Braun, J. ; Dingeldey, M. ; Durlanik, S. ; Matzmohr, N. ; Ponikwicka-Tyszko, D. ; Wolczynski, S. ; Rahman, N. A. ; Taniuchi, I. ; Schlickeiser, S. ; Giesecke-Thiel, C. ; Blankenstein, T. ; Na, I.-K.DKFZ* ; Thiel, A. ; Frentsch, M.

2025
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adr9331

Abstract: T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.

Keyword(s): CD8-Positive T-Lymphocytes: immunology (MeSH) ; CD8-Positive T-Lymphocytes: metabolism (MeSH) ; CD40 Ligand: metabolism (MeSH) ; CD40 Ligand: genetics (MeSH) ; CD40 Ligand: immunology (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; CD40 Antigens: metabolism (MeSH) ; CD40 Antigens: genetics (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; Neoplasms: immunology (MeSH) ; Neoplasms: metabolism (MeSH) ; Neoplasms: pathology (MeSH) ; Neoplasms: genetics (MeSH) ; Cytotoxicity, Immunologic (MeSH) ; Signal Transduction (MeSH) ; Caspase 8: metabolism (MeSH) ; CD40 Ligand ; CD40 Antigens ; Caspase 8

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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